4′-Trifluoromethylbiphenyl-4-carboxaldehyde

Step A:Preparation 5; (R, S)-1-(4'-Trifluoromethyl-biphenyl-4-yl)-ethano; Step A. 4'-Trifluoromethyl-biphenyl-4-carbaldehyde; To an ambient temperature solution of 4- (trifluoromethyl)phenylboronic (4.64 g, 24.43 mmol) in dioxane/water (15/15 mL) is added 4-bromo-benzaldehyde (4.42 g, 22.21 mmol), tetrabutylammonium bromide (7.16 g, 22.21 mmol, potassium carbonate (7.67 g, 55.53 mmol) and is degassed for 10 min. Palladium (II) (748 mg, 1.11 mmol) is added and the reaction mixture is heated to 70 °C. After 2 h TLC (20percent EtOAc/hexane) indicates complete consumption of starting material. The reaction is cooled to room temperature diluted with water and extracted with EtOAc (3 x 200 mL). The combined organic extracts are washed with brine, dried (MgS04), filtered, concentrated and chromatographed (330 g Si02, 5percent EtOAc/Hexanes) to yield the title compound (5.54 g, 94percent). Bromobenzaldehyde (1 eq, 0.95 mmol), 4-(Trifluoromethyl) phenylboronic acid (1.1 eq, 1.05 mmol), palladium (II) acetate, TBAB (1 eq, 0.95 mmol) and KGeneral procedure: In a 10 mL glass tube containing a Teflon-coated stir bar was placed p-bromobenzaldehyde 2e (0.05 g, 0.27 mmol, 1 equiv), phenylboronic acid 1a (0.05 g, 0.40 mmol, 1.5 equiv), 2M KGeneral procedure: A 50mL round-bottomed flask was charged with aryl halides (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3 (1.25 mmol), Ni(TFA)2 (0.025 mmol), β-diketone ligand (0.05 mmol), PPh3 (0.05 mmol), 1.5 g of the ionic liquid (IL) and 0.5 g of H2O. Then, the mixture was stirred at 80 open to the atmosphere. The reaction was monitored by TLC and then stopped after the starting material was completely consumed. Next, the mixture was diluted with water (10 mL) and extracted with ether (310 mL). The combined organic layers were washed with brine (310 mL), dried over MgSO4, and concentrated in vacuum. The cross coupling products were not the only product of the reaction. A small amount of homo-coupled products and removal boron product from boric acids were observed. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 10:1).General procedure: A mixture of compound 1 (3g, 16.21mmol), phenylboronic acid (2.57 g, 21.08 mmol), anhydrous potassium carbonate (KA 3 L 3-neck flask fitted with top stirrer, condenser and argon inlet/outlet was charged with 4-trifluoromethylbenzene boronic acid (90.0 g, 0.474 mol), 4- bromobenzaldehyde (83.29 g, 0.450 mol) and 1, 2-dimethoxyethane (1.3 L), followed by 2M aqueous sodium carbonate (474 mL) and palladium acetate (5.32 g, 0.0237 mol). The stirring mixture was heated to reflux for 4 h under argon, then allowed to cool to room temperature over 16 h. The reaction mixture was filtered through hyflo. The filtrate was diluted with saturated brine and extracted 3x with ethyl acetate. The combined extracts were dried over magnesium sulfate and filtered through hyflo, giving a clear orange filtrate which was evaporated to a solid (ca. 120g, crude). Flash chromatography (silica, 10-50percent dichloromethane in pet. ether, 10percent steps) gave a white solid which dissolved in hexane (500mL) on boiling. Crystallisation, finally in ice, gave the title compound as a solid which was filtered off, washed with ice cold hexane and dried, (86.33g, 77percent). 'H-NMR (CDCl3) 6 7.77-8. 03 (8H, m), 10.09 (1H, s).The preparation method of the biphenyl compound is:4.625 g (25 mmol) p-bromobenzaldehyde, 9.495 g (50 mmol)P-trifluoromethylbenzeneboronic acid, 1.445 g (1.25 mmol) of tetrakis(triphenylphosphine)palladium, 13.8 g (100 mmol) of potassium carbonate, 100 mL of ethylene glycol dimethyl ether and 15 mL of water are mixed.Nitrogen was pumped out three times and reacted at 110 degrees for 24 hours.After the reaction is completed, it is extracted with dichloromethane, and the organic phase is washed with water.Washed with saturated saline, Dry over anhydrous magnesium sulfate, The product was isolated by column chromatography (3.878 g).The yield was about 62percent.4-bromobenzaldehyde 1a (1.60 g, 8.8 mmol), 4-(trifluoromethyl)phenylboronic acid 1b (2.0 g, 10.5 mmol), fourTriphenylphosphine palladium (508mg, 0.44mmol)And sodium carbonate (2.33g, 22.0mmol)Soluble in a mixed solution of 34mL ethylene glycol dimethyl ether and water (V/V=15/2), The reaction was carried out at 90° C. under argon protection for 12 hours. The reaction solution was concentrated under reduced pressure and 200 mL of water was added.The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A).4'-(trifluoromethyl)-[1, 1'-biphenyl]-4-carbaldehyde 1c (1.19 g, white solid) was obtained, yield: 55.0percent.Reference Example 6-2 4'-trifiuoromethy.biphenyi-4-carbaldehyde (Compound 25}Pd(PPhStep 1: commercially available vancomycin (100 mg) and DIPEA (30 muL) were dissolved in 3 mL of DMF, to give a turbid solution, which was heated to 50 C to become clear. 4'-trifluoromethyl-biphenyl-4-carboxaldehyde (30 mg) was added, and the reaction mixture was heated under stirring for 4h. Then, NaCNBH3 (8 mg), 1 mL of methanol and 30 muL of TFA were added at room temperature. The reaction was stirred overnight, and monitored by HPLC. The reaction mixture was added with diethyl ether (50 mL) to generate precipitates, which was filtered to give a crude. The crude was purified by reverse-phase C18 HPLC, and lyophilized to give Van-c(40 mg) as a white solid. HPLC: C18 column (5 mum, 4.6 x 250 mm), UV detection at 214 nm, elution conditions: a gradient of 2-90% acetonitrile containing 0.1% v/v TFA over 30 min. HRMS (ESI+) calculated for C80H84Cl2F3N9O24 1681.4958, found 841.7475[M+2H]2+.General procedure: Compound 2a (2.55 ml, 25.00 mmol) was slowly added to the methanol15mlsolution and 2, 3, 5, 6-tetraaminopyridine hydrochloride (1.24 g, 5.0 mmol) was added to the above mixture. Then, the pH of the solution was adjusted to 1-2 by hydrochloric acid. A large number of khaki-solid were formatted with refluxing and stirring about 6h. After the reaction sufficient, it was cooled to the room temperature, filtered, washed with a small amount of methanol 3 times, and then placed it in a vacuum oven for 5h, the pure product was obtained as an orange-yellow solid 3a.10.001 g (40.0 mmol) under a nitrogen atmosphereP-trifluoromethylbenzaldehydeDissolved in 37.9 mL (308 mmol) of 2, 6-dimethylaniline and stirred at room temperature for 30 minutes.Subsequently, while maintaining a nitrogen atmosphere at a temperature of 80 C, 1.8 mL of concentrated hydrochloric acid was slowly added dropwise over 1 h, and after the completion of the dropwise addition, the temperature was raised to 150 C for 24 hours to obtain a crude product.That is, the first reaction mixture.The first reaction mixture was cooled to room temperature, neutralized by adding 25 mL of an aqueous sodium hydroxide solution (10 wt%), and extracted with dichloromethane to obtain an aqueous phase and an organic phase. The separated aqueous phase was dichloromethane. Wash at least three times.The organic phase was combined, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Finally, the organic phase is poured into ethanol.A white precipitate (8.542 g) was obtained.The yield is about 45%.

Molecular Weight:250.21
XLogP3:3.9
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:250.06054939
Monoisotopic Mass:250.06054939
Topological Polar Surface Area:17.1
Heavy Atom Count:18
Complexity:271
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes